In this application, we will characterize the modulation of synaptic plasticity in response to acute stress. In particular, we will use electrophysiological and pharmacological tools and knockout mice to examine long-term potentiation of glutamatergic and GABAergic synapses in the ventral tegmental area (VTA), a key region required for processing rewarding and aversive stimuli under physiological conditions, and also required for addiction to drugs of abuse. I expect our studies to contribute at two levels. First, we will define alterations in the basic synaptic and circuit properties of this brain region after stress. Second, we will link these alterations to stress-induced reinstatement of drug-seeking. In this application, I will focus on the effects of stress on VTA synapses. First we will identify the cellular changes in the VTA that follow a brief stressful stimulus. We will compare different forms of stress and test the time course of stress effects on synapses. Our preliminary data suggest that stress modifies VTA synapses by releasing endogenous opioid peptides, and we will explore this idea. Finally, we will use the molecular information gained in these experiments to promote or block synaptic plasticity in the VTA in vivo while assessing the ability of a brief stress to trigger reinstatement of drug-seeking. These experiments will test for the first time the hypothesis that synaptic changes occurring in the VTA are essential for stressful stimuli to elicit drug-seeking behavior. If my hypothesis is correct, our work will suggest novel molecular targets for therapeutics designed to interfere with the neuroadaptations caused by stress. PUBLIC HEALTH RELEVANCE: We have identified a cellular mechanism in a reward and addiction center of the brain, called the ventral tegmental area (VTA), that could contribute to the development of addiction and relapse to drugs of abuse. When the VTA is exposed to an addictive drug, changes in the synapses of the VTA lead to maladaptive neuronal responses that appear to be rewarding and powerfully compel behavioral responses to drugs. Intriguingly, stress appears able to trigger some of the same cellular changes in the VTA seen after addictive drugs, perhaps suggesting a way that stress promotes relapse in human substance abusers. By studying the cellular responses to these drugs and to stress, we can better understand the mechanisms underlying stress and addiction and improve human health by contributing to treatments for drug addiction.